Targeted Drug Benefits Some Patients with Advanced Lung Cancer
The drug crizotinib (Xalkori) substantially lengthens the amount of time some patients with advanced lung cancer live without their disease progressing, according to findings from the first large clinical trial to test the targeted therapy.
Initial results from the trial were presented Sunday at the European Society for Medical Oncology Congress (ESMO) in Vienna, Austria.
The Food and Drug Administration (FDA) approved crizotinib last year to treat patients with advanced non-small cell lung cancer (NSCLC) whose tumors have a specific genetic mutation. The approval was based on smaller, nonrandomized trials that showed crizotinib could shrink tumors in many patients with the mutation—a genetic rearrangement involving the ALK gene.
Until now, crizotinib had not been shown to prolong progression-free or overall survival compared with standard chemotherapy.
"The results from the phase I and phase II trials were pretty remarkable," said lead investigator, Dr. Alice Shaw of Massachusetts General Hospital. "We had high tumor response rates, which were impressive for just a single agent."
A large randomized trial was necessary, Dr. Shaw explained, to confirm that the tumor responses translated into meaningful outcomes and to answer questions about whether patients whose tumors had this genetic mutation were more sensitive to any therapy, not just crizotinib.
The results from the phase I and phase II trials were pretty remarkable. We had high tumor response rates, which were impressive for just a single agent.
—Dr. Alice Shaw
"Patients who received crizotinib did significantly better," she said. Progression-free survival was more than twice as long in patients treated with crizotinib compared with those who received chemotherapy—docetaxel (Taxotere) or pemetrexed (Alimta)—7.7 months versus 3 months.
Nearly 350 patients were enrolled in the trial, which involved 105 centers in 21 countries and was funded by the drug's manufacturer, Pfizer. Patients in the trial had advanced NSCLC that had returned after their initial treatment and their tumors had the ALK gene rearrangement. A number of studies have shown that tumors in about 4 to 5 percent of patients with NSCLC have the mutation.
The results may be enough to support a change in the drug's regulatory status. The FDA's earlier approval was an accelerated approval, meaning the drug was likely to benefit patients and address an unmet clinical need.
With such approvals, however, the agency requires data from larger trials to confirm that the drug has a clinical benefit and to ensure that unanticipated side effects do not outweigh any clinical improvements. Pfizer has notified the FDA of the trial results, the company said, and will provide the agency with the complete data when available.
Questions about Overall Survival
The ultimate goal of treatment, of course, is to lengthen overall survival. At this point, the trial has not shown that treatment with crizotinib does that any better than standard chemotherapy. And in large part because of the trial's design, there's a good chance that it won't be able to show an improvement, according to several researchers.
Patients in the trial who were randomly assigned to receive either docetaxel or pemetrexed and whose disease began to progress were allowed to cross over to treatment with crizotinib. The crossover rate, Dr. Shaw noted, was 87 percent.
It's still early in the trial, so nothing definitive about overall survival can be said yet. But with that extent of crossover, "really, the chemo arm is just like the crizotinib arm," Dr. Shaw added.
Dr. Alice Shaw presents results from the first large clinical trial to test crizotinib in patients with advanced lung cancer.
The failure to show an overall survival benefit should not dampen enthusiasm for crizotinib with these patients, stressed Dr. Ramaswamy Govindan of Siteman Cancer Center in St. Louis. It's "entirely possible" that overall survival is improved with crizotinib, Dr. Govindan continued, but the crossover may make it impossible to see in this trial. "Unfortunately, that's just the way things are," he said.
No new concerns about the drug's safety were raised in the trial. Consistent with earlier trials of crizotinib, visual disturbances—often described as floating streams of light in patients' peripheral vision—were the most common side effect, along with diarrhea and nausea. But more patients who received chemotherapy stopped treatment due to side effects.
"At every level, crizotinib was superior to chemotherapy," Dr. Shaw said, including improvements in symptoms, delay in the onset of new symptoms, and general quality of life.
"From an oncologists' standpoint, it's really gratifying to see patients reporting a better quality of life in what is essentially an incurable disease," she said.
Historically, even following dramatic tumor reductions with crizotinib treatment—including complete tumor eradication—the disease almost always returns.
The situation closely parallels what has been seen in patients with advanced NSCLC whose tumors have mutations in the EGFR gene. Many of these patients initially have excellent responses to gefitinib (Iressa) or erlotinib (Tarceva), but the tumors almost always come back, explained Dr. Giuseppe Giaccone of NCI's Center for Cancer Research.
One potential escape route for tumors may be the development of additional mutations in the ALK gene that interfere with crizotinib's ability to bind to its target. "But that doesn't seem to be the major mechanism," Dr. Giaccone said. Alterations in other key genes that can fuel cancer cell proliferation, including EGFR and MET, also appear to allow tumors to resume growing, he added.
Ways to potentially overcome this resistance are already being studied in human trials.
Data from early stage trials of second-generation ALK-targeted drugs, for example, were also presented at the ESMO meeting. In a small phase I trial testing the experimental drug LDK378, tumor responses were seen in 81 percent of NSCLC patients whose tumors had the ALK mutation and whose disease had returned after crizotinib treatment.
Crizotinib's rapid ascent from the lab to the clinic is 'a great model for modern drug development.'
—Dr. Ramaswamy Govindan
Other approaches include targeting ALK and EGFR, either with a single drug that inhibits both targets or combinations of drugs. For example, Dr. Giaccone and his CCR colleagues are part of a phase I trial testing the combination of crizotinib and the experimental agent dacomitinib in patients with advanced lung cancer, including patients with EGFR and ALK mutations. Dacomitinib inhibits EGFR and other members of the same growth factor family. Early findings from the phase I trial were presented at ESMO.
Combining targeted drugs and further subdividing patients into molecularly defined subgroups will only increase from this point on, Dr. Giaccone stressed.
Dr. Govindan called crizotinib's rapid ascent from the lab to the clinic "a great model for modern drug development." It demonstrates that "patient selection is critical," he said.
NCI cooperative group trials are already being planned to test crizotinib as the first-line therapy in patients with metastatic NSCLC with ALK mutations, he said. Pfizer has also initiated a phase III trial, PROFILE 1014, testing crizotinib as a first-line treatment in patients with ALK rearrangements.
Beyond ALK and EGFR
Patients with a different gene rearrangement may also benefit from crizotinib, according to another early-phase study presented at the ESMO meeting. In the trial, patients with advanced NSCLC whose tumors had rearrangements in the ROS1 gene, which occur in less than 2 percent of patients, also had substantial tumor responses.
Crizotinib "has remarkable activity [in these patients], nearly identical to what's been seen in patients with ALK rearrangements," explained Dr. Shaw, who was also an investigator on the trial.
Another gene, KRAS, is among the most frequently mutated genes in patients with the most common type of NSCLC, adenocarcinoma, and some studies suggest that KRAS mutations are associated with a poor prognosis. Results from the phase II GALAXY trial, also presented at the ESMO meeting, suggested that the drug ganetespib may have greater efficacy than standard chemotherapy in patients with adenocarcinoma and in patients with KRAS mutations whose disease has returned following initial treatment.
Ganetespib targets heat-shock protein (HSP) 90, a "chaperone" protein that helps other proteins carry out their functions. The drug is a second-generation HSP90 inhibitor that does not appear to have the toxicity issues of the first-generation HSP90 inhibitors, said the trial's lead investigator, Dr. Suresh Ramalingam of the Winship Cancer Institute in Atlanta.
Further follow-up is needed before investigators can confirm a benefit, Dr. Ramalingam cautioned. Earlier this year, results from a clinical trial of another targeted therapy, selumetinib, also suggested it may improve survival in NSCLC patients with KRAS mutations.
Both trials offer some much-needed hope. "This is the biggest molecular subset of lung cancer patients," Dr. Ramalingam said. "They're in serious need of good treatment options."